Bladder cancer currently ranks 6th in incidence among all cancers in the United States (4th in men and 12th in women) (9). The disease is rare prior to age 35, and two thirds of cases occur in people aged 65 or older. The huge excess in men is among the most prominent epidemiologic features of bladder cancer. Men overall have a fourfold excess of bladder cancer compared with women, and the male excess is observed to a somewhat comparable degree across all major racial-ethnic groups (8,9).

Bladder cancer is a disease for which non-Hispanic whites are at very high risk relative to other racial groups. In the
United States from 2002 to 2006, for example, the age-adjusted incidence rate of bladder cancer in non-Hispanic white men was more than twice that in black or Hispanic men. Asian-American men had rates that were lower still, roughly one third that of non-Hispanic white men (10). Women showed a somewhat comparable pattern by race ethnicity, albeit at substantially lower absolute-risk levels (Fig. 15.1).

Some population-based cancer registries classify cancer patients according to social class characteristics based on their places of residence. Specifically, census information on income and/or educational levels of residents in the neighborhoods where cancer patients reside is used to rank cancer cases. In the Los Angeles County Cancer Registry, patients are placed into one of five social-class groupings. In general, high social class individuals, whether white or black or either sex, have a higher risk of bladder cancer (Fig. 15.2) (11).

In the United States, the incidence of bladder cancer in both men and women has been relatively stable during the past 30 years. There is no clear indication of declining or increasing incidence among non-Hispanic whites or African Americans of either sex (12,13).

The uroepithelial cells lining the human bladder can become transformed to tumor cells with different histopathologies. Approximately 95% of tumors of the urinary bladder in the United States are of transitional cell type. The remaining 5% include primarily squamous, glandular, or undifferentiated cell type tumors (8). In contrast, in Egypt and parts of the Middle East, squamous cell carcinoma of the bladder constituted up to 76% of all bladder cancer diagnoses in early 1970s, when infection with Schistosoma haematobium was endemic, and decreased to approximately one third of all confirmed bladder cancer cases in 2003 to 2007, reflecting decreasing prevalence of schistosomiasis (14).

Transitional cell carcinoma occurs in two distinct morphologic forms, which have different natural histories and prognoses. Almost two thirds of transitional cell bladder cancers diagnosed in the Western world are papillary noninfiltrating morphology (i.e., superficial cancer). The remaining transitional cell carcinomas invade the underlying stroma of the bladder (i.e., invasive cancer).

Although various industries and occupations have been linked to bladder cancer in epidemiologic studies, by far the most important, at least historically, is the synthetic dye industry. The first synthetic dye, aniline purple, made from aniline, an arylamine present in coal tars, was accidentally formulated in
the 1860s. By the late 1800s, synthetic textile dye production was a major industry. The first anecdotal reports of bladder cancer occurring among employees in these chemical dye workers were published in 1895, and many others in the United States and Europe followed. Experimental evidence that oral ingestion of 2-naphthylamine, an arylamine extensively used in the manufacturing of industrial dyes, could cause bladder cancer in dogs fueled further interest in a possible etiologic association (15).

Nonetheless, the first systematic epidemiologic evidence that arylamine-exposed chemical dye workers had a large and unequivocal increase in bladder cancer risk was not published until 1954 in London, by Case et al. (2). They observed approximately a 20-fold increase in bladder cancer risk in such workers compared to the general population and concurrently showed that rubber workers, another occupational group with extensive exposure to 2-napthylamine and to benzidene, a chemically related compound, also had substantial elevation in bladder cancer risk.

Other industries and occupations that appear to be at high risk of bladder cancer based on observations from multiple epidemiologic studies include the leather industry, commercial painters, hair dressers, truck drivers, and aluminum workers (16,17). In fact, many of these associations can be linked to workers in these occupations or industries with exposure to the same arylamines, which have been proven to be human bladder carcinogens in other settings.

The earliest epidemiologic studies on cigarette smoking and bladder cancer were conducted in the 1950s (3,4). Scores of such studies have provided data on this relationship, although not all were designed specifically for that purpose. Although epidemiologic methods and statistical analytic strategies have improved dramatically since those original studies and much more detail is now known about this relationship, the general conclusion of these first studies was correct: cigarette smokers, overall, increase their bladder cancer risk some two-to threefold compared to lifelong nonsmokers. This approximate increase in risk seems to extend across many populations around the world, including multiple racial-ethnic groups. There have been a number of reviews summarizing studies contributing to our understanding of these relationships, and we will not repeat that review here (18,19). Nonetheless, some additional generalizations can be made about this relationship. Risk of bladder cancer increases with increasing number of cigarettes smoked on a daily basis and with increasing duration of smoking, although it is unclear if this relationship is strictly linear. The risk of bladder cancer decreases after people quit their smoking habit, but there is no indication that the risk among former smokers returns to the level of a lifetime nonsmoker even many years after cessation (18). Although cigarette smoking clearly increases bladder cancer risk among both men and women, relative risk appears to be higher in women for a given dose and duration of smoking (20), a finding that is supported by biomarker data on smoking-related carcinogens (21). If inhalation patterns, tar content of cigarettes, or filters modify bladder cancer risk among smokers, the impact of these effects must be very modest as they are not easily detectable by epidemiologic methods. Finally, the impact of pipe and cigar smoking on bladder cancer risk appears to be substantially less than among cigarette smokers, whereas smokeless tobacco use does not appear to affect risk at all.

Although the reason that cigarette smoking causes bladder cancer is unproven, it very likely is due to the presence of carcinogenic arylamines in cigarette smoke, especially 2-naphthylamine and 4-aminobiphenyl (4-ABP), a potent bladder carcinogen (21). One of the most fascinating features of bladder cancer epidemiology is that, despite the clear importance of cigarette smoking in bladder cancer development as noted above, there exist a number of populations worldwide with high smoking rates and high lung cancer rates, but relatively low bladder cancer rates (18). In fact, even among different racial-ethnic groups with comparable smoking habits living in the same geographic area, there can be substantial variation in bladder cancer risk.

At the most, only 50% of the bladder cancer burden in a given population can be attributed to tobacco smoking. The search for nonsmoking causes of bladder cancer was the goal of numerous studies launched in the last 40 years, and no credible hypothesis has emerged until recently. Using hemoglobin adducts of selected arylamines as biomarkers of exposure, the Los Angeles study demonstrates that among lifelong nonsmokers, bladder cancer risk increases with increasing exposure to 4-ABP, presumably from diffuse, as-yet-unidentified sources in the environment (22). Even more interesting is the finding that lifelong nonsmokers who develop bladder cancer are also exposed to higher levels of selected anilines that hitherto had not been linked to human bladder cancer (23).

Environmental tobacco smoke (ETS) exposure (“passive” smoking) is one of the sources for arylamines. Elevated levels of 4-ABP have been seen among lifelong nonsmokers with ETS exposure (24,25). Population-based studies that examined the relation of ETS exposure to bladder cancer risk generally reported null results (26,27). However, ETS exposure in childhood, especially for women, was associated with an elevated bladder cancer risk in several studies (28,29,30).

Hair dyes represent another substantial source of arylamine exposure in humans. In developed countries, including North America, Europe, and Japan, up to 40% of adult women use hair dyes on a regular basis. There are three major types of hair dyes: permanent dyes, semipermanent dyes, and temporary rinses. Permanent dyes are the most common, accounting for roughly three fourths of all hair dye use. Many commercial brands of hair dyes are mutagenic and some are known to contain recognized animal carcinogens (31).

Early studies of bladder cancer risk in hair dye users, conducted in the 1970s and 1980s, reported largely null results. Few of these studies differentiated among the three major types of hair dyes (permanent, semipermanent, or temporary rinses). In the recent Los Angeles study, personal use of hair dyes was assessed according to the types of hair dyes normally used. Women who reported regular and sustained use of permanent hair dyes were found to experience an increased risk of bladder cancer comparable in level to women who smoked. Risk increased with increasing frequency of hair dye applications and with increasing duration of use (32). The New Hampshire study found a similar, but statistically nonsignificant positive association between hair dye and bladder cancer in women (33). Among women who were smokers as well as permanent hair dye users, the level of increased bladder cancer risk was approximately the sum of the individual effects from smoking and use of permanent hair dyes (34). This latter statistical observation is compatible with the notion of a common etiologic pathway (i.e., arylamine exposure) linking these two seemingly distinct environmental exposures to bladder cancer development.

4-ABP may exist as a contaminant in commercially produced 1,4-phenylenediamine, a key component of many permanent hair dyes. A recent study detected the presence of 4-ABP (in parts per billion) in 8 of 11 commercial brands of hair dyes in the United States, and found nursing mothers who were current users of hair dyes to exhibit significantly elevated levels of 4-ABP DNA adducts in epithelial cells from breast milk relative to nursing mothers who were not currently using hair dyes (35).

Although our understanding of bladder cancer epidemiology and etiology focuses around the important contribution of exposure from various sources to carcinogenic arylamines, a number of other potential risk or protective factors have also been extensively explored over the past several decades in relationship to bladder cancer occurrence.